Otitis media (middle ear inflammation) ranks first among the most common diagnoses requiring a physician's office visit and recent estimates indicate that virtually all children (99%) will experience a least one episode of otitis media (OM) by age 2. The disease progresses in many children to recurrent infections and chronic inflammation, often with complications and sequalae that include persistent hearing loss nd communication disorders. Streptococcus pneumoniae (Spn), is one of the foremost human pathogens and is the primary nasopharynx, the initial event in the induction of OM and the mechanisms which effect the transition for a colonized state to invasion of the middle ear and the induction of the disease state by Spn are not known. The long term objectives of this proposal are to delineate the pathogenic mechanisms involved in Spn adherence, colonization, and invasion of the middle ear and to develop a scientific rationale for the design of novel diagnostic and prevention strategies. The specific aims of this proposal are: 1) To continue to define the role of Spn neuraminidase in the pathogenesis of OM and to assess whether it is a protective antigen and a potential protein-based vaccine candidate, and whether neuraminidase inhibitors are effective in the prevention of Spn nasopharyngeal colonization of OM. 2) To assess the efficacy of lacto-N-neotetraose, a Spn carbohydrate receptor analog, as an anti-infective for nasopharyngeal colonization. 3) To continue to define the mechanisms whereby influenza A virus affects Spn adherence, colonization, and OM. These aims are designed to delineate the initial interaction, adherence, and colonization which represents the first in a series of steps that culminates in otitis media. These studies may suggest avenues for blocking interaction of Spn with host cells either by immunization or direct intervention blockade with isolated receptor moieties or bacterial adhesin components.